Pyrimidine derivatives for treating malaria

ABSTRACT

The pyrimidine derivatives of formula I ##STR1## wherein R 1  is naphthyl, substituted naphthyl or substituted phenyl; R 2  is hydrogen or lower alkoxy; and A is an optionally present ethylene or 1,3-propylene, and wherein the diaminopyridine group has the exo-configuration when A is present, are described. These compounds are useful as antibacterial agents, antimalarial agents and antitumor agents, and can be used in combination with sulfonamides in the control of bacterial infections.

This is a continuation of application Ser. No. 837,447 filed Mar. 7,1986, now abandoned, which is a divisional of Ser. No. 598,119 filedApr. 9, 1984, now U.S. Pat. No. 4,590,270.

BRIEF SUMMARY OF THE INVENTION

The invention is related to compounds of the formula ##STR2## wherein R¹is naphthyl, substituted naphthyl, or substituted phenyl; R² is hydrogenor lower alkoxy; and A is an optionally present ethylene or1,3-propylene, and wherein the diaminopyrimidine group has theexo-configuration when A is present.

These compounds are useful as antibacterial agents, and antimalarialagents.

Pharmaceutical compositions containing the above compounds, processesfor preparing the above compounds, and methods for treating bacterialinfections, and malaria using the above compounds also form a part ofthe invention.

DETAILED DESCRIPTION OF THE INVENTION

The invention is concerned with pyrimidine derivatives of the formula##STR3## wherein R¹ is naphthyl, substituted naphthyl or substitutedphenyl; R² is hydrogen or lower-alkoxy; and A is an optionally presentethylene or 1,3-propylene, and wherein the diaminopyrimidine group hasthe exo-configuration when A is present and salts thereof.

These compounds are useful as antibacterial agents, and antimalarialagents.

The invention is furthermore concerned with pharmaceutical compositionswhich contain a compound of formula I, a method for treating bacterialinfections, or malaria which comprises administering a compound offormula I, and a process for the preparation of the compounds of formulaI and intermediates products used in connection therewith.

More specifically, the invention relates to a pharmaceutical compositioncomprising an effective amount of a compound of the formula I or a saltthereof ##STR4## wherein R¹ is naphthyl, substituted naphthyl, orsubstituted phenyl; R² is hydrogen or lower-alkoxy; and A is optionallypresent ethylene or 1,3-propylene, and wherein the diaminopyrimidinegroup has the exo-configuration when A is present, and an inert carriermaterial.

The invention also relates to a method for treating bacterial infectionswhich comprises administering to a host in need of such treatment aneffective amount of a compound of the formula I or a salt thereof##STR5## wherein R¹ is naphthyl, substituted naphthyl or substitutedphenyl; R² is hydrogen or lower-alkoxy; and A is an optionally presentethylene or 1,3-propylene, and wherein the diaminopyrimidine group hasthe exo-configuration when A is present.

The invention also relates to a method for treating malaria whichcomprises administering to a host in need of such treatment an effectiveamount of a compound of the formula I or a salt thereof ##STR6## whereinR¹ is naphthyl, substituted naphthyl or substituted phenyl; R² ishydrogen or lower-alkoxy; and A is an optionally present ethylene or1,3-propylene, and wherein the diaminopyrimidine group has theexo-configuration when A is present.

When R¹ is a substituted naphthyl or substituted phenyl, it ispreferably singly or multiply substituted by lower-alkyl, loweralkylthio, lower alkoxy, halogen, amino, lower-alkyl-amino ordi(lower-alkyl)-amino, nitro, trifluoromethyl, lower-alkoxycarbonyl,carboxyl, cyano or --CONHR³ in which R³ is hydrogen, lower-alkyl or theresidue which is formed by removal of an amino group from an amino acidR³ NH₂. The naphthyl residue can be α-naphthyl or p-naphthyl. The term"lower" denotes substituents with 1-6 carbon atoms. Alkyl groups can bestraight-chain or branched. Examples of such groups are methyl, ethyl,propyl, isopropyl and butyl. Preferred substituted phenyl substituentsare 4-methoxyphenyl, 3,5-dimethoxyphenyl and 3,4,5-trimethoxyphenyl.Examples of amino acids R³ NH₂ are glycine, β-alanine, aspartic acid andglutamic acid. A preferred group of compounds of formula I are those inwhich R¹ is substituted phenyl. Furthermore, there are preferablycompounds of formula I in which A is ethylene. These compounds can berepresented by the formula ##STR7##

In another respect the invention is concerned with compounds of theformula ##STR8## The compounds of formula I can be prepared inaccordance with the invention by

(a) treating a compound of the formula ##STR9## wherein X is chlorine orbromine and R¹ and A are as described above, with a reducing agent, or

(b) reacting a compound of the formula ##STR10## with a compound of theformula R¹¹ -Z, in which R¹¹ is naphthyl or substituted naphthyl orsubstituted phenyl, the substituents of which are inert under thereaction conditions, and Z is halogen or nitro, or

(c) reacting a compound of formula II with an alkali metallower-alkylate, and, if desired, modifying a substituent contained in R¹in the reaction product.

Suitable reducing agents for the removal of the chlorine or brominesubstituent X from a compound of formula II are hydrogen in the presenceof noble metal catalysts, such as Pd/carbon; or nascent hydrogen, e.g.Zn/glacial acetic acid, or amalgamated zinc in NaOH. The reduction canbe undertaken in a manner known per se. The catalytic hydrogenation isconveniently carried out at room temperature in an inert solvent, e.g.aqueous acetic acid, or ethanol. The reduction with nascent hydrogen isconveniently carried out while heating, e.g. at temperatures up to thereflux temperature of the reaction mixture.

The N-substitution of a compound of formula III can be effected in amanner known per se. There are conveniently employed in this processvariant compounds of formula R¹¹ -Z in which there are containedsubstituents which are inert under the reaction conditions and whichactivate the substituent Z for the reaction with the compound III. Thereaction is conveniently carried out in an inert solvent, such asacetonitrile or dimethyl sulfoxide in the presence of an acid-bindingagent, such as alkali or alkaline earth hydroxides or carbonates whileheating, e.g. up to the reflux temperature of the reaction mixture.There are preferably employed in this process variant compounds offormula R¹¹ -Z in which R¹¹ is substituted by lower-alkoxy, halogen,nitro, trifluoromethyl, cyano or lower-alkoxycarbonyl. Z is preferablyhalogen, especially fluorine.

The reaction of a compound of formula II with an alkali metal loweralkylate can be undertaken by heating a compound of formula II with analkali metal lower alkylate in the alcohol corresponding to thealkylate, e.g. to temperatures up to the reflux temperature. Examples ofalkali metal lower alkylates are sodium and potassium methylate orethylate.

Substituents contained in R¹ in the thus-obtained compounds of formula Ican be modified. For example, an alkoxycarbonyl group can be saponifiedto the carboxy group or can be transformed into a carbamoyl group; acarboxy group can be amidated to a group CONHR³ ; a nitro group can bereduced to the amino group, whereupon the amino group can be alkylatedor diazotized and replaced with a halogen atom. These reactions can becarried out according to methods and under conditions which aregenerally known for the saponification of ester groups, amidation ofcarboxylic acid or carboxylic acid ester groups, reduction of nitrogroups to amino groups alkylation of the latter as well as replacementof aromatic amino groups with other groups (Sandmeyer reaction).Compounds of formula I in which R¹ is carboxyl or --CONHR³ areconveniently manufactured by saponifying an obtained compound of formulaI in which R¹ is lower-alkoxycarbonyl and optionally reacting thethus-obtained carboxylic acid with a lower-alkylamine or an amino acidR³ NH₂ in the presence of condensation agents, such asdicyclohexylcarbodiimide or carbonyldiimidazole.

The compounds of formula I can be converted into acid addition salts,especially those which are customary in pharmaceutical preparations, bytreatment with inorganic acids (e.g. hydrochloric acid, sulphuric acid,phosphoric acid etc) or organic acids (e.g. formic acid, acetic acid,succinic acid, lactic acid, citric acid, maleic acid, fumaric acid,tartaric acid, methanesulphonic acid, p-toluenesulphonic acid etc).

The compounds of formula II also form a part of the invention. They canbe prepared as indicated in the following Formula Scheme and asdescribed in detail in the Examples. ##STR11##

By reacting a correspondingly substituted aniline or a naphthylamine (1)with acrylic acid ethyl ester there is obtained the tertiary amine (2)and therefrom by Dieckmann condensation hydrolysis and decarboxylationof the β-ketoester (3) the piperidone (4). The Knoevenagel condensationwith the cyanoacetic acid ethyl ester of (4) or (5) (Tetrahedron 28,155-165 [1972]) and Bull. Chem. Soc. Japan 44, 1708-9 [1971]) yields (6)which is converted into (7) by reduction of the conjugated double bond.The reduction of compounds (6) in which X is present is convenientlycarried out with LiAlH₄, in which case (7) is obtained as an isomermixture in which the cyanoacetic acid residue has the endo- orexo-configuration. The exo-isomer which is required for the preparationof the preferred compounds IA can be separated in a manner known per se,e.g. by chromatography. Condensation of (7) with guanidine yields thepyrimidone (8) from which II can be obtained by halogenation. Thereaction (7)→(8 )→II can be carried out by analogy with known procedureswhich are described e.g. in German Offenlegungsschrift 2 003 578.

The compounds of formula I are pharmacologically active. In particular,they are active antibacterially and against malaria pathogens.

The compounds of formula I are useful as antibacterial agents and, areuseful as antimalarial agents.

The compounds of formula I inhibit dihydrofolate reductase andpotentiate the antibacterial activity of sulfonamides. They can also beused in combination with antibacterially-active sulfonamides as agentsfor the control of bacterial infections.

It has been found thatexo-2,4-diamino-5-[8-(3,5-dimethoxyphenyl)-8-azabicyclo[3.2.1]oct-3-yl]pyrimidine(A) is active in an inhibitory concentration IC₅₀ of 3.3 mmol in thecase of dihydrofolate reductase from E. coli. In the case of in vitroexperiments an minimum inhibitory concentration of 0.1-1.6 μg/ml hasbeen determined for compound A against Bacteroides fragilis strains.Against the malaria pathogen P. falciparum compound A in vitro showed anID₅₀ of 1.4 μg/l (strain T9) and 0.9 μg/l (strain 13). In comparison tothis, values of 79 and 45 μg/l, respectively, were determined for theknown pyrimethamine.

Examples of sulfonamides which are potentiated by the compounds offormula I are those of the pyrimidine, isoxazole, oxazole and pyrazineseries such as sulfadiazine, sulfadimethoxine, sulfadoxine,sulfamerazine, sulfameter, sulfamethazine,6-methoxy-4-sulfanilamidopyrimidine, sulfamethoxazole, sulfisoxazole,3-sulfanilamido-4,5-dimethyl-isoxazole, sulfamoxole and sulfalen.

The compounds of formula I can be used as pharmaceutical preparations inadmixture with an organic or inorganic inert carrier material suitablefor oral, rectal or parenteral application, e.g. water, gelatine, gumarabic, lactose, starch, magnesium stearate, talc, vegetable oils,polyalkylene glycols, Vaseline, etc. The pharmaceutical preparations canbe present in solid form, e.g. as tablets, dragees, suppositories,capsules; in semi-solid form, e.g. as salves; or in liquid form, e.g. assolutions, suspensions or emulsions. If desired, they are sterilizedand/or contain further adjuvants, such as preserving, stabilizing,wetting or emulsifying agents, agents for the improvement of flavour,salts for varying the osmotic pressure or buffer substances. Thepreparation of the pharmaceutical compositions can be effected in themanner which is familiar to the person skilled in the art.

In the prophylaxis of malaria, the compounds of formula I, e.g. compoundA can be used in dosages of from 25 mg to 50 mg for an adult.Preferably, the compounds of formula I are used in combination with along-acting sulfonamide such as sulfadoxine. Suitably, a combination of1 part by weight of compound A and 10 to 20 parts by weight ofsulfadoxine are used. In the prophylaxis of malaria, a dosage of 500 mgonce per week of such a combination can be used for an adult. In thetreatment of malaria, a single dosage of 1000-1500 mg of the abovecombination can be used for an adult.

The following Examples further illustrate the invention.

EXAMPLE 1

180 mg ofexo-4-chloro-2,6-diamino-5-[8-(4-methoxyphenyl)-8-azabicyclo[3.2.1]oct-3-yl]pyrimidinewere dissolved in 20 ml of a mixture of acetic acid and water (1:1) andhydrogenated in the presence of 100 mg of 10% palladium/carbon catalystuntil hydrogen was no longer taken up or the reaction was complete inaccordance with thin-layer chromatography. The catalyst was removed byfiltration over a filter aid and the filtrate was evaporated to dryness.The residue was suspended in water and the suspension was adjusted to pH9 by addition of aqueous ammonium hydroxide. Filtration yielded aproduct which was chromatographed on silica gel with chloroform/methanol(9:1). Subsequent crystallization from methanol yieldedexo-2,4-diamino-5-[8-(4-methoxyphenyl)-8-azabicyclo[3.2.1]oct-3-yl]pyrimidineof melting point 242°.

The starting material was prepared as follows:

A. 3.0 g of 8-(4-methoxyphenyl)-8-azabicyclo[3.2.1]octan-3-one weredissolved in 6 ml of dimethylformamide and treated with 1.8 ml ofcyanoacetic acid ethyl ester, 0.2 ml of piperidine and 58 mg ofβ-alanine. The mixture was heated to 50° for 28 hours while stirring.After cooling to room temperature, the mixture was diluted with ether,washed four times with water, dried over sodium sulfate and concentratedunder reduced pressure. Chromatography of the residue on 250 g of silicagel with hexane/ethyl acetate (3:2) yielded ethylcyano-[8-(4-methoxyphenyl)-8-azabicyclo[3.2.1]octanylidene]acetate as awhite solid, melting point 121°-122° (from isopropyl ether).

B. 1.82 g of the thus-obtained compound were dissolved in 22 ml oftetrahydrofuran under argon. The mixture was cooled to -10°, treatedwith 110 mg of lithium aluminum hydride, stirred at -10° C. for 10minutes and thereafter treated with saturated aqueous ammonium chloridesolution and water. The thick suspension was filtered through filterpaper and the residue was washed thoroughly with ethyl acetate. Theorganic phase of the filtrate was washed twice with water, dried oversodium sulfate and concentrated. The residue was chromatographed on 200g of silica gel (230-400 mesh) with hexane/ethyl acetate (3:1). Therewere obtained 630 mg of ethylrac-(exo)-α-cyano-[8-(4-methoxyphenyl)-8-azabicyclo[3.2.1octane]octane]-3-acetate as an oil besides the endo-isomer.

C. An ethanolic sodium ethoxide solution was freshly prepared bydissolving 10 mmol of sodium in 12 ml of absolute ethanol under argon.The solution was treated with 10 mmol of guanidine hydrochloride andstirred at room temperature for 20 minutes. Thereafter, 5 mmol of thepreviously obtained α-cyanoacetate (exo-isomer) were added. The mixturewas heated to reflux for 4 hours, cooled to room temperature and left inthe refrigerator overnight. The solid was filtered off, washed well withwater and dried. There was obtainedexo-2,6-diamino-5-[8-(4-methoxyphenyl)-8-azabicyclo[3.2.1]oct-3-yl]-4(3H)-pyrimidinone,melting point above 260° C. (from methanol/chloroform).

D. 10 mmol of the previously obtained pyrimidinone were suspended in 15ml of POCl₃ and treated with 2.6 ml of N,N-dimethylaniline. The mixturewas heated to reflux (105° C.) for 1.5 hours, and cooled to roomtemperature. About 2/3 of the phosphorus oxychloride were removed underreduced pressure. The viscous residue was added cautiously to ice andthe aqueous suspension obtained was left to stand at room temperaturefor 5 days. The pH of the reaction mixture was adjusted to about 10 byby addition of 25% aqueous ammonium hydroxide solution, the product wasfiltered off and washed with water and subsequently with ethanol.Thereafter, the product was chromatographed on silica gel withchloroform/methanol (9:1). From 310 mg ofexo-2,6-diamino-5-[8-(4-methoxyphenyl)-azabicyclo[3.2.1]oct-3-yl]-4-(3H)-pyrimidinonethere were obtained 180 mg ofexo-4-chloro-2,6-diamino-5-[8-(4-methoxyphenyl)-8-azabicyclo[3.2.1]oct-3-yl]pyrimidine.

EXAMPLE 2

In analogy to Example 1, from 1.6 g ofexo-4-chloro-2,6-diamino-5-[8-(3,5-dimethoxyphenyl)-8-azabicyclo[3.2.1]-oct-3-yl]pyrimidinethere were obtained 980 mg ofexo-2,4-diamino-5-[8-(3,5-dimethoxyphenyl)-8-azabicyclo[3.2.1]oct-3-yl]pyrimidine,melting point 261°-262° C. (from methanol).

The starting material was prepared in analogy to the process describedin Example 1, paragraphs A-D, starting from8-(3,5-dimethoxyphenyl)-8-azabicyclo[3.2.1]octan-3-one via

ethylcyano-[8-(3,5-dimethoxyphenyl)-8-azabicyclo[3.2.1]octanylidene]acetate,melting point 116° C. (from isopropyl ether),

ethylrac-(exo)-α-cyano-[8-(3,5-dimethoxyphenyl)-8-azabicyclo[3.2.1]octane-3]acetate,mp. 92°-93° C. (from ethanol) and

exo-2,6-diamino-5-[8-(3,5-dimethoxyphenyl)-8-azabicyclo[3.2.1]oct-3-yl]-4-(3H)-pyrimidinone,melting point 193°194° C. (from ethanol/water).

The ethylcyano-[8-(3,5-dimethoxyphenyl)-8-azabicyclo[3.2.1]octanylidene]acetatecan be reduced as follows:

0.7 g of lithium were dissolved in 150 ml of dry, distilled ammonia at-78° C. and treated dropwise under nitrogen during 20 minutes with asolution of 8.9 g of ethylcyano-[8-(3,5-dimethoxyphenyl)-8-azabicyclo[3.2.1]octanylidene]acetateand 2.35 g of phenol in 50 ml of dry tetrahydrofuran. The mixture wasleft to stir for 30 minutes, whereupon 5 g of ammonium chloride wereadded. The ammonia was distilled off, the residue was taken up in ethylacetate, filtered and the filtrate was evaporated. Chromatography of thecrude product on silica gel with hexane/ethyl acetate (4:1) gave,besides a small amount of endo-isomer, 7.8 g of ethylrac-(exo)-α-cyano-[8-(3,5-dimethoxyphenyl)-8-azabicyclo[3.2.1]octane-3]acetateof melting point 92°-93° C. (from ethanol).

EXAMPLE 3

21.5 g of2,4-diamino-6-chloro-5-[1-(4-methoxyphenyl)-4-piperidinyl]pyrimidinewere dissolved in 350 ml of a mixture of acetic acid and water (1:1) andhydrogenated in the presence of 7 g of 10% palladium/carbon catalystuntil the hydrogen uptake ceased or the reaction was complete inaccordance with thin-layer chromatography. The catalyst was filtered offover a filter aid and the filtrate was evaporated to dryness. Theresidue was suspended in water and the pH was adjusted to 9 by additionof aqueous ammonium hydroxide. Filtration yielded a crude product whichwas chromatographed on silica gel with chloroform/methanol (19:1). Therewere obtained 8.7 g of2,4-diamino-5-[1-(4-methoxyphenyl)-4-piperidinyl]pyrimidine of meltingpoint 224°-225° C.

The starting material was prepared as follows:

A. 32.3 g of diethyl 3,3'-[(4-methoxyphenyl)-imino]dipropionate in 40 mlof xylene were added under argon to a freshly prepared solution ofsodium ethoxide in absolute ethanol (2.3 g of sodium in 55 ml ofethanol). The mixture was heated slowly to about 110° C., by which meansthe ethanol was distilled off. Thereafter, the mixture was heated for afurther 2 hours. The mixture was cooled to room temperature and pouredon to ice. After neutralization with concentrated hydrochloric acid, themixture was extracted with ether. The extract was washed three timeswith water, dried over sodium sulfate and evaporated. The product waschromatographed on silica gel with hexane/ethyl acetate (9:1) andyielded ethyl 1-(p-methoxyphenyl)-4-oxo-3-piperidinecarboxylate as ayellow oil.

B. 57.9 g of the thus-obtained carboxylate were heated to reflux for 1hour in 225 ml of 6N hydrochloric acid. After cooling to about 2° C.,the mixture was neutralized by addition of 110 ml of 50% aqueous sodiumhydroxide and extracted with ether. The organic phase was washed threetimes with water, dried over sodium sulfate and concentrated. Theresidue was recrystallized from ethanol. There was obtained1-(p-methoxyphenyl)-4-piperidone, melting point 69° C. (from ethanol).

C. 20.5 g of 1-(p-methoxyphenyl)-4-piperidone were dissolved in 200 mlof benzene and treated with 1.2 g of acetic acid, 0.85 ml of piperidineand 14.5 g of cyanoacetic acid ethyl ester. The mixture was heated toreflux for 3 hours, the reaction water being removed by means of aDean-Stark trap. After cooling to room temperature, the mixture wasdiluted with ether and washed three times with 2N sodium bicarbonatesolution and once with water. The organic extract was dried over sodiumsulfate and concentrated. The oily residue was triturated with ethanoland left in the refrigerator overnight. The solid was filtered off andwashed with ethanol and isopropyl ether, there being obtained 24.1 g ofproduct. Recrystallization from ethanol yielded ethylcyano-[1-(p-methoxyphenyl)-4-piperidinylidene]acetate, melting point 87°C.

D. 22.5 g of the thus-obtained compound were dissolved in 500 ml ofethanol and 200 ml of methanol and hydrogenated up to the end of thehydrogen uptake with 5 g of 10% palladium-carbon catalyst (50% in water)while stirring vigorously at room temperature. After filtration over afilter aid, the filtrate was evaporated under reduced pressure and theresidue was crystallized from a small amount of isopropyl ether. Therewas obtained ethyl α-cyano-[1-(4-methoxyphenyl)-4-piperidine]acetate,melting point 65° C.

E. The thus-obtained compound was condensed with guanidine in accordancewith Example 1, paragraph (C). There was obtained2,6-diamino-5-[1-(4-methoxyphenyl)-4-piperidinyl]-4-(3H)-pyrimidinone,melting point 308° C. (from dimethylformamide/water).

F. In analogy to Example 3, paragraph (C), from the thus-obtainedpyrimidinone there was obtained2,4-diamino-6-chloro-5-[1-(4-methoxyphenyl)-4-piperidinyl]pyrimidine,melting point 254° C. (decomposition, from ethanol).

EXAMPLE 4

In analogy to Example 3, from 5.7 g of2,4-diamino-6-chloro-5-[1-(3,5-dimethoxyphenyl)-4-piperidinyl]pyrimidinethere were obtained 4.8 g of crude2,4-diamino-5-[1-(3,5-dimethoxyphenyl)-4-piperidinyl]pyrimidine, fromwhich there were obtained 3.2 g of pure product of melting point 217° C.after chromatography and recrystallization from methanol.

The starting material was prepared as follows:

A. A mixture of 50.4 g of 3,5-dimethoxyaniline, 6.0 g of copper (I)chloride, 46.0 g of acetic acid and 100 g of ethyl acrylate was heatedto reflux for 19 hours while stirring. After cooling to roomtemperature, the mixture was diluted with about 30 ml of methylenechloride and washed successively three times with 300 ml of water, threetimes with 300 ml of 10% aqueous ammonium hydroxide and again threetimes with 300 ml of water. The organic phase was dried over sodiumsulfate and evaporated under reduced pressure. The residue waschromatographed on 1.5 kg of silica gel (230-400 mesh) with hexane/ethylacetate (4:1) under medium pressure. There were obtained 70.9 g ofdiethyl 3,3'-(3,5-dimethoxyphenyl)-imino]dipropionate as a yellow oil,b.p. 139° C./0.09 mm.

B. From diethyl 3,3'-[(3,5-dimethoxyphenyl)-imino]-dipropionate therewere obtained in analogy to Example 3, paragraph (A), ethyl1-(3,5-dimethoxyphenyl)-4-oxo-3-piperidinecarboxylate, melting point60°-61° C.

C. 12.52 g of the previously mentioned carboxylate were heated on thesteam-bath in 81.6 ml of 1N sodium hydroxide solution while stirringvigorously for 2 hours. After cooling to room temperature, the mixturewas extracted with ether, the extract was washed twice with water, driedover sodium sulfate and evaporated. The residue was chromatographed onsilica gel with hexane/ethyl acetate (4:1) and yielded 4.8 g of1-(3,5-dimethoxyphenyl)-4-piperidone as a yellow oil.

D. In analogy to Example 3, paragraph (C), from the previously obtainedpiperidone there were obtained ethylcyano-[1-(3,5-dimethoxyphenyl)-4-piperidinylidene]acetate, melting point115° C. (from methanol).

E. 19.2 g of the previously mentioned compound were dissolved in 400 mlof ethyl acetate and hydrogenated with 6 g of 10% palladium/carboncatalyst (50% in water). 19.7 g of ethylα-cyano-1-(3,5-dimethoxyphenyl)-4-piperidine]acetate were obtained as anoil.

F. Ethyl α-cyano-[1-(3,5-dimethoxyphenyl)-4-piperidine]acetate wascondensed with guanidine in analogy to Example 1, paragraph (C). Therewas obtained2,6-diamino-5-[1-(3,5-dimethoxyphenyl)-4-piperidinyl]-4-(3H)-pyrimidinone,melting point above 250° C. (from dimethylformamide/water).

G.2,6-Diamino-5-[1-(3,5-dimethoxyphenyl)-4-piperidinyl]-4-(3H)-pyrimidinonewasconverted in analogy to Example 3, paragraph (D), into2,4-diamino-6-chloro-5-[1-(3,5-dimethoxyphenyl)-4-piperidinyl]pyrimidine,melting point 241°-242° C. (from methanol/chloroform).

EXAMPLE 5

In analogy to Example 1, from 0.4 g ofexo-4-chloro-2,6-diamino-5-[8-(3,4,5-trimethoxyphenyl)-8-azabicyclo[3.2.1]oct-3-yl]pyrimidinethere were obtained 250 mg ofexo-2,4-diamino-5-[8-(3,4,5-trimethoxyphenyl)-8-azabicyclo[3.2.1]-oct-3-yl]pyrimidine,m.p. 247°-248° C. (from methanol).

The starting material was prepared in analogy to the process describedin Example 1, paragraph A-D, starting from8-(3,4,5-trimethoxyphenyl)-8-azabicyclo[3.2.1]octan-3-one, m.p.144°-145° C. (from methanol), via

ethylcyano-[8-(3,4,5-trimethoxyphenyl)-8-azabicyclo[3.2.1]octanylidene]acetate,m.p. 107°-108° C.,

ethylrac-(exo)-α-cyano-[8-(3,4,5-trimethoxyphenyl)-8-azabicyclo[3.2.1]octane-3]acetate(yellowish oil) and

exo-2,6-diamino-5-[8-(3,4,5-trimethoxyphenyl)-8-azabicyclo[3.2.1]oct-3-yl]-4-[3H]-pyrimidinone,m.p. 265° C. (dec.) from methanol-water).

EXAMPLE 6

In analogy to Example 3, from 5.6 g of2,4-diamino-6-chloro-5-[1-(3,4,5-trimethoxyphenyl)-4-piperidinyl]pyrimidinethere were obtained 1.0 g of2,4-diamino-5-[1-(3,4,5-trimethoxyphenyl)-4-piperidinyl]pyrimidine, m.p.239°-240° C. (from methanol).

The starting material was prepared in analogy to the process describedin Example 3, paragraphs C-F, from1-(3,4,5-trimethoxyphenyl)-4-piperidine via

ethyl 2-cyano-2-[1-(3,4,5-trimethoxyphenyl)-4-piperidinylidene]acetate,m.p. 111° C., yellow crystals from isopropanol,

ethyl 2-cyano-2-[1-(3,4,5-trimethoxyphenyl)-4-piperidinyl]acetate,colourless oil, and

2,6-diamino-5-[1-(3,4,5-trimethoxyphenyl)-4-piperidinyl]-4-3(H)-pyrimidinone,m.p. >250° C. (dec.) (from ethanol).

EXAMPLE 7

A mixture of 1 g of 2,4-diamino-5-(4-piperidyl)pyrimidine, 0.71 g of4-fluoronitrobenzene and 0.7 g of potassium carbonate in 20 ml ofacetonitrile were boiled at reflux for 72 hours with the exclusion ofmoisture. After cooling to room temperature, the mixture was filtered,the residue was washed with water, methanol and ether and recrystallizedfrom dimethyl sulfoxide. This gave 1.36 g of2,4-diamino-5-[1-(p-nitrophenyl)-4-piperidinyl]-pyrimidine. Meltingpoint above 250° C.

Preparation of the starting material:

A solution of 26 g of 2,4-diamino-5-(1-benzyl-4-piperidinyl)pyrimidinein 700 ml of ethanol and 20 ml of acetic acid was hydrogenated over 5 gof Pd/C 10% at room temperature and normal pressure up to the standstillof the hydrogen uptake, whereupon it was filtered off from catalyst. Thefiltrate was concentrated and the crystalline residue was dissolved in100 ml of water. Chromatography on Dowex 1 (×10 200-400 mesh) (a cationexchange resin) gave 2,4-diamino-5-(4-piperidyl)-pyrimidine of meltingpoint 230°-231° C. (dec.) (from water).

EXAMPLE 8

1 g of 2,4-diamino-5-[1-(p-nitrophenyl)-4-piperidinyl]pyrimidine wasdissolved in 50 ml of water and 10 ml of conc. hydrochloric acid,treated with 700 mg of iron powder and stirred at 80° C. for 45 minutes.The mixture was filtered over a filter aid, the filtrate was cooled to0°-5° C., diazotized with 210 mg of sodium nitrite in 2 ml of water andthe resulting diazonium solution was added dropwise at 0°-5° C. to asolution of copper (I) chloride (prepared from 250 mg of copper (II)sulfate pentahydrate, 80 mg of sodium chloride and 70 mg of sodiumbisulfite) in 0.8 ml of hydrochloric acid. Thereafter, the reactionmixture was heated at 90° C. for 1 hour, treated with active carbon,filtered and concentrated to 50 ml. The residue was neutralized withammonium hydroxide, filtered off and the product obtained afterdistilling off the water was chromatographed on silica gel with CHCl₃/EtOH (9:1). Recrystallization from ethanol yielded2,4-diamino-5-[1-(p-chlorophenyl)-4-piperidinyl]pyrimidine of meltingpoint 254°-255° C.

EXAMPLE 9

In analogy to Example 7, from 2.0 g of2,4-diamino-5-(4-piperidyl)-pyrimidine and 1.7 g of 4-fluorobenzoic acidethyl ester there were obtained 3.1 g of ethylp-[1-(2,4-diamino-5-pyrimidinyl)-4-piperidinyl]benzoate, m.p. above 250°C. (from dimethyl sulfoxide).

EXAMPLE 10

2.1 g of the benzoate obtained in Example 9 was dissolved in a mixtureof 15 ml of conc. hydrochloric acid and 20 ml of water and stirred at60° C. overnight. The resulting suspension was cooled to roomtemperature, adjusted to pH 8 by addition of ammonia and filtered.Washing the residue with water and drying gavep-[1-(2,4-diamino-5-pyrimidinyl]-4-piperidinyl]benzoic acid of meltingpoint 310°-311° C. (with decomposition).

EXAMPLE 11

In analogy to Example 7, from 500 mg of2,4-diamino-5-(4-piperidinyl)-pyrimidine and 300 mg of4-fluorobenzonitrile in 10 ml of dimethyl sulfoxide there were obtained250 mg of 2,4-diamino-5-[1-(p-cyanophenyl)-4-piperidinyl]pyrimidine,m.p. >250° C. (from dimethyl sulfoxide).

EXAMPLE 12

In analogy to Example 1, from 4.1 g ofexo-4-chloro-2,6-diamino-5-[8-(2,5-dimethoxyphenyl)-8-azabicyclo[3.2.1]oct-3-yl]pyrimidinethere were obtained 2.4 g ofexo-2,4-diamino-5-[8-(2,5-dimethoxyphenyl)-8-azabicyclo[3.2.1]oct-3-yl]-pyrimidine,m.p. 270° C. (from methanol).

The starting material was prepared in analogy to the process describedin Example 1, paragraph A-D, starting from 8-(2,5dimethoxyphenyl)-8-azabicyclo[3.2.1]octan-3-one, m.p. 66°-67° C. (fromether), via

ethyl cyano-[8-(2,5dimethoxyphenyl)-8-azabicyclo[3.2.1]oct-anylidene]acetate (yellowishoil),

ethyl rac-(exo)-α-cyano-[8-(2,5dimethoxyphenyl)-8-azabicyclo[3.2.1]octane-3]acetate (oil) andexo-2,6-diamino-5-[8](2,5dimethoxyphenyl)-8-azabicyclo[3.2.1]oct-3-yl]-4-[3H]-pyrimidinone, m.p.164° C. (from methanol-water).

EXAMPLE 13

In analogy to Example 1, from 0.18 g ofexo-4-chloro-2,6-diamino-5[8-(1-naphthyl)-8-azabicyclo[3.2.1]oct-3-yl]pyrimidinethere were obtained 55 mg ofexo-2,4-diamino-5-[8-(1-naphthyl)-8-azabicyclo[3.2.1]oct-3-yl]pyrimidine,m.p. 245°-248° C. (from methanol).

The starting material was prepared in analogy to the process describedin Example 1, paragraph A-D, starting from8-(1-naphthyl)-8-azabicyclo[3.2.1]octan-3-one, m.p. 114°-115° C., via

ethyl cyano-[8-(1-naphthyl)-8-azabicyclo[3.2.1]octanylidene]-acetate,m.p. 111°-114° C.,

ethylrac-(exo)-α-cyano-[8-(1-naphthyl)-8-azabicyclo[3.2.1]octane-3]acetate(yellowish oil) andexo-2,6-diamino-5-[8-(1-naphthyl)-8-azabicyclo[3.2.1]oct-3-yl]-4-[3H]pyrimidinone,m.p. 275° C. (dec.) (from methanol-water).

EXAMPLE 14

In analogy to Example 1, from 0.3 g ofexo-4-chloro-2,6-diamino-5-[8-(2-naphthyl)-8-azabicyclo[3.2.1]oct-3-yl]pyrimidinethere were obtained 200 mg ofexo-2,4-diamino-5-[8-(2-naphthyl)-8-azabicyclo[3.2.1]oct-3-yl]pyrimidine,m.p. 258°-9° C. (from methanol).

The starting material was prepared in analogy to the process describedin Example 1, paragraphs A-D, starting from8-(2-naphthyl)-8-azabicyclo[3.2.1]octan-3-one, m.p. 120°-1° C., via

ethyl cyano-[8-(2-naphthyl)-8-azabicyclo[3.2.1]octanylidene]-acetate,m.p. 122°-3° C.,

ethylrac-(exo)-α-cyano-[8-(2-naphthyl)-8-azabicyclo[3.2.1]-octane-3]acetate,m.p. 126°-7° C., andexo-2,6-diamino-5-[8-(2-naphthyl)-8-azabicyclo[3.2.1]oct-3-yl]-4-[3H]pyrimidinone,m.p. 275° C. (dec.) (from methanol-water).

We claim:
 1. A method for treating malaria which comprises administeringto a host in need of said treatment an effective amount for treatingmalaria of a compound of the formula I or a salt thereof ##STR12##wherein R¹ is naphthyl, or naphthyl or phenyl singly substituted bylower-alkyl, lower alkylthio, lower alkoxy, halogen, amino,lower-alkylamino, di(lower-alkyl)-amino, nitro, trifluoromethyl,lower-alkoxycarbonyl, carboxyl, cyano or --CONHR³ wherein R³ ishydrogen, lower-alkyl or the residue which is formed by removal of anamino group from an amino acid R³ NH₂ ; or phenyl di- or tri-substitutedby lower-alkoxy; R² is hydrogen or lower-alkoxy; and A is an optionallypresent ethylene or 1,3-propylene, and wherein the diaminopyrimidinegroup has the exo-configuration wherein A is present.
 2. A method inaccordance with claim 1, wherein R¹ is phenyl singly, di- ortri-substituted by lower alkoxy.
 3. A method in accordance with claim 2,wherein R¹ is 4-methoxyphenyl; 3,5-dimethoxyphenyl or3,4,5-trimethoxyphenyl.
 4. A method in accordance with claim 3, whereinthe compound of formula I isexo-2,4-diamino-5-[8-(3,5-dimethoxyphenyl)-8-azabicyclo[3.2.1]oct-3-yl]pyrimidine.5. A method in accordance with claim 3, wherein the compound of formulaI is 2,4-diamino-5-[1-(3,5-dimethoxyphenyl)-4-piperidinyl]pyrimidine.